Sign up to receive free email alerts when patent applications with chosen keywords are publishedSIGN UP

Abstract:

This invention provides a convenient method for converting oximes into
enamides. The process does not require the use of metallic reagents.
Accordingly, it produces the desired compounds without the concomitant
production of a large volume of metallic waste. The enamides are useful
precursors to amides and amines. The invention provides a process to
convert a prochiral enamide into the corresponding chiral amide. In an
exemplary process, a chiral amino center is introduced during
hydrogenation through the use of a chiral hydrogenation catalyst. In
selected embodiments, the invention provides methods of preparing amides
and amines that include the 1,2,3,4-tetrahydro-N-alkyl-1-naphthalenamine
or 1,2,3,4-tetrahydro-1-naphthalenamine substructure.

Claims:

1-44. (canceled)

45. A mixture comprising: ##STR00070## wherein R4 is a member
selected from substituted or unsubstituted aryl and substituted or
unsubstituted heteroaryl; Q.sup.- is an anion; e and f are independently
selected numbers from 0 to 1; and x and y are selected from R and S, such
that when x is R, y is R, and when x is S, y is S.

46. The mixture according to claim 45 wherein A is present in said
mixture in a diastereomeric excess of at least 90% relative to B.

47. The mixture according to claim 46 wherein A is present in said
mixture in a diastereomeric excess of at least 98% relative to B.

48. The mixture according to claim 45 wherein x and y are R.

49. The mixture according to claim 45 wherein x and y are S.

50. The mixture according to claim 45 wherein x is S and y is R.

51. A pharmaceutical formulation comprising a mixture according to claim
45 and a pharmaceutically acceptable carrier.

Description:

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a U.S. National Phase Application of
PCT/US2007/065659 filed Mar. 30, 2007 and claims priority under 35 U.S.C.
§119(e) to U.S. Provisional Patent Application No. 60/787,837 filed
Mar. 31, 2006, which applications are incorporated herein by reference in
their entirety for all purposes.

FIELD OF THE INVENTION

[0002] This invention relates to processes suitable for the large-scale
preparation of enantiomerically- or diastereomerically-enriched chiral
amides and amines prepared by these processes.

BACKGROUND OF THE INVENTION

[0003] Enantiomerically-enriched chiral primary amines are commonly used
as resolving agents for racemic acids, as chiral auxiliaries for
asymmetric syntheses and as ligands for transition metal catalysts used
in asymmetric catalysis. In addition, many pharmaceuticals, such as
sertraline, contain chiral amine moieties. Effective methods for the
preparation of such compounds are of great interest to the pharmaceutical
industry. Particularly valuable are processes that allow for the
preparation of each enantiomer or diastereomer, in enantiomeric or
diastereomeric excess, as appropriate, from prochiral or chiral starting
materials.

[0004] Methods are available for the preparation of enantiomerically
enriched amines. For example, the addition of organometallic reagents to
imines or their derivatives is reported by Watanabe et al., Tetrahedron
Asymm. (1995)6:1531; Denmark et al., J. Am. Chem. Soc. (1987) 109:2224;
Takahashi et al., Chem. Pharm. Bull. (1982) 30:3160; and the addition of
organometallic reagents to chiral oxazolidines is disclosed by
Mokhallalatiet et al., Tetrahedron Lett. (1994) 35:4267. Although some of
these methods are widely employed, few are amenable to large-scale
production of amines.

[0005] Other approaches involve optical resolution of a single enantiomer
or diastereomer from a mixture. Resolution may be conducted through
stereoselective biotransformation or by the formation of diastereomeric
salts that are separated by crystallization. The utility and
applicability of resolution methods relying on selective
recrystallization are often limited by the lack of availability of
appropriate chiral auxiliaries. In addition, resolution processes upon
racemic mixtures afford a maximum yield of 50% for either stereoisomer.
Therefore, the resolution of racemic mixtures is generally viewed as an
inefficient process.

[0006] The preparation of an enantiomerically-enriched amine via
conversion of a precursor oxime to the corresponding enamide, which is
subsequently converted to the amine through asymmetric hydrogenation and
deprotection, has been described (WO 99/18065 to Johnson et al.). The
processes are, however, not of general applicability to a wide range of
substrates. Moreover, many of the recognized processes require a large
excess of metallic reagent to effect the conversion. The result is the
generation of significant amounts of solid metal waste, a trait that is
undesirable for large-scale production processes.

[0007] Therefore, a cost-efficient, scalable method for the conversion of
oximes to corresponding enamides, which does not rely on a metallic
reagent, is needed. The facile, high yield conversion of readily
accessible oximes to the corresponding enamides without the use of
metallic reagents would be a valuable step towards the large-scale
synthesis of chiral amides and amines. The current invention addresses
this and other needs.

SUMMARY OF THE INVENTION

[0008] The present invention provides an efficient and convenient method
for the conversion of an oxime to the corresponding enamide. The method
of the invention accomplishes the desired conversion without the use of a
metallic reagent. The method is appropriate for large-scale synthesis of
enamides, amides, amines, and their derivatives.

[0009] Thus, in a first aspect, the current invention provides a method
for converting an oxime into an enamide. The method includes contacting
the oxime with a phosphine and an acyl donor, under conditions
appropriate to convert the oxime into the enamide. The method produces
enamides in high yields and is generally applicable across a wide range
of oxime structures. The enamides are readily converted to the
corresponding amines. In an exemplary route, described in greater detail
herein, the enamide is reduced to the corresponding amide, which is
subsequently deacetylated to provide the amine.

[0010] The method is particularly useful for the large-scale synthesis of
bioactive species, such as those having the
1,2,3,4-tetrahydro-N-alkyl-1-naphthalenamine or
1,2,3,4-tetrahydro-1-naphthalenamine substructure. Examples of bioactive
compounds with this substructure include sertraline and sertraline
analogs, and the trans isomers of sertraline, norsertraline and analogs
thereof. Sertraline, (1S,4S)-cis
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine, is
approved for the treatment of depression by the United States Food and
Drug Administration, and is available under the trade name ZOLOFT®
(Pfizer Inc., NY, N.Y., USA). In human subjects, sertraline has been
shown to be metabolized to (1S,4S)-cis
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine, also known
as desmethylsertraline or norsertraline.

[0011] Enamides provide a convenient precursor to compounds that include
the 1,2,3,4-tetrahydro-N-alkyl-1-naphthalenamine or
1,2,3,4-tetrahydro-1-naphthalenamine substructure. Accordingly, in a
second aspect, the present invention provides a method of converting an
oxime having the formula:

##STR00001##

into an enamide having the formula:

##STR00002##

[0012] In the formulae above, the symbol R4 represents substituted or
unsubstituted aryl or substituted or unsubstituted heteroaryl. The symbol
R5 represents H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted
or unsubstituted heteroaryl or substituted or unsubstituted
heterocycloalkyl. The method includes contacting said oxime with a
phosphine and an acyl donor under conditions appropriate to convert said
oxime to said enamide.

[0013] In a third aspect, the invention provides a mixture comprising:

##STR00003##

In the formulae above, Q.sup.- is an anion. The indices e and f are
independently selected numbers from 0 to 1. The indices x and y
independently represent (R) or (S). In an exemplary embodiment, when x is
(R), y is (R) and when x is (S), y is (S). In another exemplary
embodiment, when x is (S), y is (R).

[0014] The present invention provides a general and efficient method for
converting oximes to enamides. Moreover, the invention provides a method
for the stereo-selective synthesis of sertraline and sertraline analogs,
and the trans isomers of sertraline, norsertraline and analogs thereof.
Additional objects, advantages and embodiments of the present invention
are set forth in the detailed description that follows.

DETAILED DESCRIPTION OF THE INVENTION

Abbreviations

[0015] As used herein, "COD" means 1,5-cyclooctadiene.

DEFINITIONS

[0016] Where substituent groups are specified by their conventional
chemical formulae, written from left to right, they equally encompass the
chemically identical substituents, which would result from writing the
structure from right to left, e.g., --CH2O-- is preferably intended
to also recite --OCH2--.

[0017] The term "alkyl," by itself or as part of another substituent,
means, unless otherwise stated, a straight- or branched-chain, or cyclic
hydrocarbon radical, or combination thereof, which may be fully
saturated, mono- or polyunsaturated and can include mono-, di- and
multivalent radicals, having the number of carbon atoms designated (i.e.
C1-C10 means one to ten carbons). Examples of saturated
hydrocarbon radicals include, but are not limited to, groups such as
methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,
sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs
and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and
the like. An unsaturated alkyl group is one having one or more double
bonds or triple bonds. Examples of unsaturated alkyl groups include, but
are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl,
2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and
3-propynyl, 3-butynyl, and the higher homologs and isomers. The term
"alkyl," unless otherwise noted, also preferably include those
derivatives of alkyl defined in more detail below, such as "heteroalkyl."
Alkyl groups that are limited to hydrocarbon groups are termed
"homoalkyl". The term "alkyl", as used herein refers to alkyl, alkenyl
and alkynyl moieties, each of which can be mono-, di- or polyvalent
species. Alkyl groups are preferably substituted, e.g., with one or more
groups referred to hereinbelow as an "alkyl group substituent."

[0018] The term "alkylene" by itself or as part of another substituent
means a divalent radical derived from an alkane, as exemplified, but not
limited, by --CH2CH2CH2CH2--, and further includes
those groups described below as "heteroalkylene." Typically, an alkyl (or
alkylene) group will have from 1 to 24 carbon atoms, with those groups
having 10 or fewer carbon atoms being preferred in the present invention.
A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene
group, generally having eight or fewer carbon atoms.

[0019] The terms "alkoxy," "alkylamino" and "alkylthio" (or thioalkoxy)
are used in their conventional sense, and refer to those alkyl groups
attached to the remainder of the molecule via an oxygen atom, an amino
group, or a sulfur atom, respectively.

[0020] The term "heteroalkyl," by itself or in combination with another
term, means, unless otherwise stated, a stable straight- or
branched-chain, or cyclic alkyl radical consisting of the stated number
of carbon atoms and at least one heteroatom selected from the group
consisting of B, O, N, Si and S, wherein the heteroatom may optionally be
oxidized and the nitrogen atom may optionally be quaternized. The
heteroatom(s) may be placed at any internal position of the heteroalkyl
group or at a terminus of the chain, e.g., the position through which the
alkyl group is attached to the remainder of the molecule. Examples of
"heteroalkyl" groups include, but are not limited to,
--CH2--CH2--O--CH3, --CH2--CH2--NH--CH3,
--CH2--CH2--N(CH3)--CH3,
--CH2--S--CH2--CH3, --CH2--CH2,
--S(O)--CH3, --CH2--CH2--S(O)2--CH3,
--CH═CH--O--CH3, --Si(CH3)3,
--CH2--CH═N--OCH3, and --CH═CH--N(CH3)--CH3.
Two or more heteroatoms may be consecutive, such as, for example,
--CH2--NH--OCH3 and --CH2--O--Si(CH3)3.
Similarly, the term "heteroalkylene" by itself or as part of another
substituent refers to a substituted or unsubstituted divalent heteroalkyl
radical, as exemplified, but not limited by,
--CH2--CH2--S--CH2--CH2-- and
--CH2--S--CH2--CH2--NH--CH2--. For heteroalkylene
groups, heteroatoms can also occupy either or both of the chain termini
(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and
the like). Still further, for alkylene and heteroalkylene linking groups,
no orientation of the linking group is implied by the direction in which
the formula of the linking group is written. For example, the formula
--C(O)2R'-- represents --C(O)2R'-- and, preferably,
--R'C(O)2--.

[0021] The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in
combination with other terms, represent, unless otherwise stated, cyclic
versions of "alkyl" and "heteroalkyl", respectively. Additionally, for
heterocycloalkyl, a heteroatom can occupy the position at which the
heterocycle is attached to the remainder of the molecule. Examples of
cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl,
1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of
heterocycloalkyl include, but are not limited to,
1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,
3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,
tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,
1-piperazinyl, 2-piperazinyl, and the like.

[0022] The terms "halo" or "halogen," by themselves or as part of another
substituent, mean, unless otherwise stated, a fluorine, chlorine,
bromine, or iodine atom. Additionally, terms such as "haloalkyl," are
meant to include monohaloalkyl and polyhaloalkyl. For example, the term
"halo(C1-C4)alkyl" is meant to include, but not be limited to,
trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and
the like.

[0023] The term "aryl" means, unless otherwise stated, a polyunsaturated,
aromatic, substituent that can be a single ring or multiple rings
(preferably from 1 to 3 rings, one or more of which is optionally a
cycloalkyl or heterocycloalkyl), which are fused together or linked
covalently. The term "heteroaryl" refers to aryl groups (or rings) that
contain from one to four heteroatoms selected from N, O, and S, wherein
the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen
atom(s) are optionally quaternized. A heteroaryl group can be attached to
the remainder of the molecule through a heteroatom. Non-limiting examples
of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl,
4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,
2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,
2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,
5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,
2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,
4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,
1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl,
and 6-quinolyl. Substituents for each of the above noted aryl and
heteroaryl ring systems are selected from the group of "aryl group
substituents" described below.

[0024] For brevity, the term "aryl" when used in combination with other
terms (e.g., aryloxy, arylthioxy, arylalkyl) preferably includes both
homoaryl and heteroaryl rings as defined above. Thus, the term
"arylalkyl" optionally includes those radicals in which an aryl group is
attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and
the like) including those alkyl groups in which a carbon atom (e.g., a
methylene group) has been replaced by, for example, an oxygen atom (e.g.,
phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the
like).

[0025] Substituents for the alkyl and heteroalkyl radicals (including
those groups often referred to as alkylene, alkenyl, heteroalkylene,
heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and
heterocycloalkenyl) are generically referred to as "alkyl group
substituents," and they can be one or more of a variety of groups
selected from, but not limited to: --OR', ═O, ═NR', --NR'R'',
--SR', -halogen, --SiR'R''R''', --OC(O)R', --C(O)R', --CO2R',
--CONR'R'', --OC(O)NR'R'', --NR''C(O)R', --NR'--C(O)NR''R''',
--NR''C(O)2R', --NR--C(NR'R''R''')═NR'''',
--NR--C(NR'R'')═NR''', --S(O)R', --S(O)2R', --S(O)2NR'R'',
--NRSO2R', --CN and --NO2 in a number ranging from zero to (2
m'+1), where m' is the total number of carbon atoms in such radical. R',
R'', R''' and R'''' each preferably independently refer to hydrogen,
substituted or unsubstituted heteroalkyl, substituted or unsubstituted
aryl, e.g., aryl substituted with 1-3 halogens, substituted or
unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups.
When a compound of the invention includes more than one R group, for
example, each of the R groups is independently selected as are each R',
R'', R''' and R'''' groups when more than one of these groups is present.
When R' and R'' are attached to the same nitrogen atom, they can be
combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. For
example, --NR'R'' is meant to include, but not be limited to,
1-pyrrolidinyl and 4-morpholinyl. From the above discussion of
substituents, one of skill in the art will understand that the term
"alkyl" includes groups with carbon atoms bound to groups other than
hydrogen, such as haloalkyl (e.g., --CF3 and --CH2CF3) and
acyl (e.g., --C(O)CH3, --C(O)CF1, --C(O)CH2OCH3, and
the like).

[0026] Similar to the substituents described for the alkyl radical,
substituents for the aryl and heteroaryl groups are generically referred
to as "aryl group substituents." The substituents are selected from, for
example: halogen, --OR', ═O, ═NR', ═N--OR', --NR'R'', --SR',
--SiR'R''R''', --OC(O)R', --C(O)R', --CO2R', --CONR'R'',
--OC(O)NR'R'', --NR''C(O)R', --NR'--C(O)NR''R''', --NR''C(O)2R',
--NR--C(NR'R''R''')═NR'''', --NR--C(NR'R'')═NR''', --S(O)R',
--S(O)2R', --S(O)2NR'R'', --NRSO2R', --CN and --NO2,
--R', --N3, --CH(Ph)2, fluoro(C1-C4)alkoxy, and
fluoro(C1-C4)alkyl, in a number ranging from zero to the total
number of open valences on the aromatic ring system; and where R', R'',
R''' and R'''' are preferably independently selected from hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl and substituted or
unsubstituted heteroaryl. When a compound of the invention includes more
than one R group, for example, each of the R groups is independently
selected as are each R', R'', R''' and R'''' groups when more than one of
these groups is present.

[0027] Two of the substituents on adjacent atoms of the aryl or heteroaryl
ring may optionally be replaced with a substituent of the formula
-T-C(O)--(CRR')q--U--, wherein T and U are independently --NR--,
--O--, --CRR'-- or a single bond, and q is an integer from 0 to 3.
Alternatively, two of the substituents on adjacent atoms of the aryl or
heteroaryl ring may optionally be replaced with a substituent of the
formula -A-(CH2)r--B--, wherein A and B are independently
--CRR'--, --O--, --NR--, --S--, --S(O)--, --S(O)2--,
--S(O)2NR'-- or a single bond, and r is an integer of from 1 to 4.
One of the single bonds of the new ring so formed may optionally be
replaced with a double bond. Alternatively, two of the substituents on
adjacent atoms of the aryl or heteroaryl ring may optionally be replaced
with a substituent of the formula --(CRR')s--X--(CR'R''')d--,
where s and d are independently integers of from 0 to 3, and X is --O--,
--NR'--, --S--, --S(O)--, --S(O)2--, or --S(O)2NR'--. The
substituents R, R', R'' and R''' are preferably independently selected
from hydrogen or substituted or unsubstituted (C1-C6)alkyl.

[0028] As used herein, the term "heteroatom" includes oxygen (O), nitrogen
(N), sulfur (S) and silicon (Si).

[0029] The symbol "R" is a general abbreviation that represents a
substituent group that is selected from substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, and
substituted or unsubstituted heterocyclyl groups.

[0030] The term "salt(s)" includes salts of the compounds which are
prepared with relatively nontoxic acids or bases, depending on the
particular substituents found on the compounds described herein. When
compounds of the present invention contain relatively acidic
functionalities, base addition salts can be obtained by contacting the
neutral form of such compounds with a sufficient amount of the desired
base, either neat or in a suitable inert solvent. Examples of base
addition salts include sodium, potassium, calcium, ammonium, organic
amino, or magnesium salt, or a similar salt. When compounds of the
present invention contain relatively basic functionalities, acid addition
salts can be obtained by contacting the neutral form of such compounds
with a sufficient amount of the desired acid, either neat or in a
suitable inert solvent. Examples of acid addition salts include those
derived from inorganic acids like hydrochloric, hydrobromic, nitric,
carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric,
dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or
phosphorous acids, and the like, as well as the salts derived from
relatively nontoxic organic acids like acetic, propionic, isobutyric,
butyric, maleic, malic, malonic, benzoic, succinic, suberic, fumaric,
lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,
tartaric, methanesulfonic, and the like. Also included are salts of amino
acids such as arginate, and the like, and salts of organic acids like
glucuronic or galactunoric acids and the like (see, for example, Berge et
al., Journal of Pharmaceutical Science, 66: 1-19 (1977)). Certain
specific compounds of the present invention contain both basic and acidic
functionalities that allow the compounds to be converted into either base
or acid addition salts. Hydrates of the salts are also included.

[0031] When the compound prepared by a method of the invention is a
pharmacological agent, the salt is preferably a pharmaceutically
acceptable salt. Examples of pharmaceutically acceptable salts are
presented hereinabove, and are generally known in the art. See, for
example, Wermuth, C., PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND
USE--A HANDBOOK, Verlag Helvetica Chimica Acta (2002)

[0032] The neutral forms of the compounds are preferably regenerated by
contacting the salt with a base or acid and isolating the parent compound
in the conventional manner. The parent form of the compound differs from
the various salt forms in certain physical properties, such as solubility
in polar solvents, but otherwise the salts are equivalent to the parent
form of the compound for the purposes of the present invention.

[0033] In addition to salt forms, the present invention provides compounds
that are in a prodrug form. Prodrugs of the compounds described herein
are those compounds that readily undergo chemical changes under
physiological conditions to provide the compounds of the present
invention. Additionally, prodrugs can be converted to the compounds of
the present invention by chemical or biochemical methods in an ex vivo
environment. For example, prodrugs can be slowly converted to the
compounds of the present invention when placed in a transdermal patch
reservoir with a suitable enzyme or chemical reagent.

[0034] As used herein, and unless otherwise indicated, the term "prodrug"
means a derivative of a compound that can hydrolyze, oxidize, or
otherwise react under biological conditions (in vitro or in vivo) to
provide the compound. Examples of prodrugs include, but are not limited
to, compounds that comprise biohydrolyzable moieties such as
biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable
carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and
biohydrolyzable phosphate analogs. Other examples of prodrugs include
compounds that comprise NO, NO2, --ONO, or --ONO2 moieties. The
term "prodrug" is accorded a meaning herein such that prodrugs do not
encompass the parent compound of the prodrug. When used to describe a
compound of the invention, the term "prodrug" may also interpreted to
exclude other compounds of the invention.

[0035] As used herein, and unless otherwise indicated, the terms
"biohydrolyzable carbamate," "biohydrolyzable carbonate,"
"biohydrolyzable ureide" and "biohydrolyzable phosphate" mean a
carbamate, carbonate, ureide and phosphate, respectively, of a compound
that either: 1) does not interfere with the biological activity of the
compound but can confer upon that compound advantageous properties in
vivo, such as uptake, duration of action, or onset of action; or 2) is
biologically inactive but is converted in vivo to the biologically active
compound. Examples of biohydrolyzable carbamates include, but are not
limited to, lower alkylamines, substituted ethylenediamines, aminoacids,
hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether
amines.

[0036] As used herein, and unless otherwise indicated, the term
"biohydrolyzable ester" means an ester of a compound that either: 1) does
not interfere with the biological activity of the compound but can confer
upon that compound advantageous properties in vivo, such as uptake,
duration of action, or onset of action; or 2) is biologically inactive
but is converted in vivo to the biologically active compound. Examples of
biohydrolyzable esters include, but are not limited to, lower alkyl
esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline
esters.

[0037] As used herein, and unless otherwise indicated, the term
"biohydrolyzable amide" means an amide of a compound that either: 1) does
not interfere with the biological activity of the compound but can confer
upon that compound advantageous properties in vivo, such as uptake,
duration of action, or onset of action; or 2) is biologically inactive
but is converted in vivo to the biologically active compound. Examples of
biohydrolyzable amides include, but are not limited to, lower alkyl
amides, α-amino acid amides, alkoxyacyl amides, and
alkylaminoalkylcarbonyl amides.

[0038] Certain compounds of the present invention can exist in unsolvated
forms as well as solvated forms, including hydrated forms. In general,
the solvated forms are equivalent to unsolvated forms and are encompassed
within the scope of the present invention. Certain compounds of the
present invention may exist in multiple crystalline or amorphous forms.
In general, all physical forms are equivalent for the uses contemplated
by the present invention and are intended to be within the scope of the
present invention.

[0039] Certain compounds of the present invention possess asymmetric
carbon atoms (optical centers) or double bonds; the racemates,
diastereomers, geometric isomers and individual isomers are encompassed
within the scope of the present invention.

[0040] As used herein, and unless otherwise indicated, a composition that
is "substantially free" of a compound means that the composition contains
less than about 20% by weight, more preferably less than about 10% by
weight, even more preferably less than about 5% by weight, and most
preferably less than about 3% by weight of the compound.

[0041] As used herein, the term "substantially free of its cis
stereoisomer" means that a mixture of a compound is made up of a
significantly greater proportion of its trans stereoisomer than of its
optical antipode. In a preferred embodiment of the invention, the term
"substantially free of its cis stereoisomer" means that the compound is
made up of at least about 90% by weight of its trans stereoisomer and
about 10% by weight or less of its cis stereoisomer. In a more preferred
embodiment of the invention, the term "substantially free of its cis
stereoisomer" means that the compound is made up of at least about 95% by
weight of its trans stereoisomer and about 5% by weight or less of its
cis stereoisomer. In an even more preferred embodiment, the term
"substantially free of its cis stereoisomer" means that the compound is
made up of at least about 99% by weight of its trans stereoisomer and
about 1% or less of its cis stereoisomer.

[0042] The graphic representations of racemic, ambiscalemic and scalemic
or enantiomerically pure compounds used herein are taken from Maehr, J.
Chem. Ed., 62: 114-120 (1985): solid and broken wedges are used to denote
the absolute configuration of a chiral element; wavy lines indicate
disavowal of any stereochemical implication which the bond it represents
could generate; solid and broken bold lines are geometric descriptors
indicating the relative configuration shown but not implying any absolute
stereochemistry; and wedge outlines and dotted or broken lines denote
enantiomerically pure compounds of indeterminate absolute configuration.

[0043] The terms "enantiomeric excess" and "diastereomeric excess" are
used interchangeably herein. Compounds with a single stereocenter are
referred to as being present in "enantiomeric excess." Those with at
least two stereocenters are referred to as being present in
"diastereomeric excess."

[0044] The compounds of the present invention may also contain unnatural
proportions of atomic isotopes at one or more of the atoms that
constitute such compounds. For example, the compounds may be radiolabeled
with radioactive isotopes, e.g., tritium (3H), iodine-125
(125I) or carbon-14 (14C). All isotopic variations of the
compounds of the present invention, whether radioactive or not, are
intended to be encompassed within the scope of the present invention.

Introduction

[0045] The present invention provides a non-metal mediated method for the
conversion of oximes to the corresponding enamides. The enamides are
formed in high yields and purities, making them suitable substrates for
homogeneous asymmetric hydrogenation, a process that affords
enantiomerically-enriched amides. The amides can be deprotected to
furnish enantiomerically-enriched amines. Either enantiomer of the amine
may be obtained by this method. Ketones and aldehydes can thus be
transformed into enantiomerically-enriched chiral amines. The process is
amenable to large-scale production.

Methods

A. Oxime to Enamide

[0046] In a first aspect, the present invention provides a method for
converting an oxime into an enamide. The method includes contacting the
oxime with a phosphine and an acyl donor, under conditions appropriate to
convert the oxime into the enamide. Exemplary conditions are set forth
herein.

[0047] In one embodiment, the oxime of use in the method of the invention
has the formula:

##STR00004##

The symbols R1, R2 and R3 represent radicals that are
independently selected from H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl and substituted or
unsubstituted heterocycloalkyl. At least two of R1, R2 and
R3 are optionally joined to form a ring system selected from
substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl and substituted or
unsubstituted heteroaryl.

[0048] In another exemplary embodiment, the oxime has the formula:

##STR00005##

The symbol Ar represents substituted or unsubstituted aryl or substituted
or unsubstituted heteroaryl. R4 is H, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl or
substituted or unsubstituted heterocycloalkyl. The index a is an integer
from 1 to 4.

[0049] In an exemplary embodiment according to this aspect, R4 is
substituted or unsubstituted aryl (e.g., phenyl). In a further exemplary
embodiment, R4 is phenyl substituted with at least one halogen atom.

[0050] In yet another exemplary embodiment, R4 has the formula:

##STR00006##

in which the symbols X1 and X2 represent independently selected
halo moieties. In a preferred embodiment, X1 and X2 are each
chloro.

[0051] In another exemplary embodiment, the oxime has the formula:

##STR00007##

wherein R4 is selected from substituted or unsubstituted aryl and
substituted or unsubstituted heteroaryl.

[0052] In a further exemplary embodiment, the oxime has the formula:

##STR00008##

[0053] The preparation of oximes is well known in the art and a wide range
of methods is known and readily practiced by those of skill in the art.
Typically, oximes are prepared by reaction of ketones or aldehydes with
hydroxylamine (or alkyloxyamine) under one of a variety of conditions.
See, e.g., Sandler and Karo, "ORGANIC FUNCTIONAL GROUP PREPARATIONS,"
Vol. 3, pp 372-381, Academic Press, New York, 1972.

[0054] In an exemplary embodiment, optically pure tetralone is converted
into the corresponding oxime according to Scheme 1.

##STR00009##

[0055] In Scheme 1, optically pure tetralone 1 is treated with
hydroxylamine hydrochloride, and sodium acetate in methanol to afford the
oxime 2. Compound 2 can either be isolated or carried forward as a
solution in a suitable solvent to the next step. In another method, a
ketone is converted to the corresponding oxime in an aromatic hydrocarbon
solvent, e.g., toluene.

[0056] According to the process of the invention, the oxime is converted
into an enamide. In an exemplary embodiment, the enamide has the formula:

##STR00010##

in which R1-R3 are as discussed above and R5 is selected
from H, substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl and substituted or unsubstituted
heterocycloalkyl.

[0057] In another exemplary embodiment, the enamide has the formula:

##STR00011##

in which R4 is selected from substituted or unsubstituted aryl and
substituted or unsubstituted heteroaryl. R5 is selected from H,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl and substituted or unsubstituted
heterocycloalkyl.

[0058] An exemplary enamide has the formula:

##STR00012##

[0059] In an exemplary embodiment according to this aspect, C-4 of the
ketone, oxime and enamide is of (S)-configuration.

[0060] In a preferred embodiment, the enamide has the formula:

##STR00013##

[0061] C-4 has a configuration selected from (R) and (S) and, in a
preferred embodiment, C-4 is of (S)-configuration. In another embodiment,
the method provides an enamide mixture including both (S)- and
(R)-enantiomers.

Acyl Donor

[0062] Acyl donors of essentially any structure are of use in the present
invention. An exemplary acyl donor has the formula:

Z--C(O)--R5

in which Z is a leaving group. R5 is a member selected from H,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl and substituted or unsubstituted
heterocycloalkyl.

[0063] In an exemplary embodiment, the acyl donor is an acid anhydride, in
which Z has the formula:

R6--C(O)--O--

in which R6 is a member selected from substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl and
substituted or unsubstituted heterocycloalkyl.

[0064] In another exemplary embodiment, R5 and R6 are
independently selected substituted or unsubstituted C1-C4
moieties.

[0065] In another embodiment, the acyl donor is an anhydride, preferably
acetic anhydride (Ac2O).

[0066] In another exemplary embodiment, the acyl donor is a member
selected from an acid chloride (Z=Cl) and an activated ester, e.g., an
N-hydroxy succinimidyl ester.

[0067] The acyl donor can be present in any useful amount and selection of
this amount is within the abilities of those of skill in the art. In an
exemplary embodiment, the acyl donor is used in an amount from about 1 to
about 3 equivalents, preferably from about 1 to about 2 equivalents and,
more preferably, from about 1 to about 1.5 equivalents relative to the
oxime substrate.

Phosphine

[0068] Phosphorus reagents, such as phosphines, of any structure are of
use in practicing the present invention. For example, in general,
phosphines have the formula:

P(Q)3

in which each Q is independently selected from H, substituted or
unsubstituted alkyl and substituted or unsubstituted aryl.

[0070] The phosphorus reagent, such as phosphine, is incorporated into the
reaction mixture in substantially any useful amount. Exemplary reactions
of the invention utilize from about 0.5 equivalents to about 5
equivalents, preferably from about 1 equivalent to about 3 equivalents
and, more preferably, from about 1.1 equivalents to about 2 equivalents
of the phosphorus reagent with respect to the carbonyl-containing
substrate.

Solvent

[0071] In an exemplary embodiment, the oxime is contacted with the
phosphorus reagents (e.g., phosphine) and the acyl donor in the presence
of an organic solvent. The solvent can be a protic or an aprotic solvent.
In a preferred embodiment, the solvent is an aprotic solvent. In a
further preferred embodiment, the aprotic solvent is an aromatic solvent
(e.g., toluene, xylene and combinations thereof).

[0072] In an exemplary embodiment, in which the oxime is compound 3, the
solvent is preferably toluene.

B. Enamide to Amide

[0073] In another aspect, the current invention provides a method for
converting an enamide to an amide. The method includes, contacting the
enamide with a hydrogenation catalyst and hydrogen or a hydrogen transfer
reagent under conditions appropriate to hydrogenate a carbon-carbon
double bond of the enamide, thereby converting the enamide to an amide.

[0074] The methods of the present invention are not limited to practice on
enamides characterized by any particular structural element or membership
within any single structural class. The methods disclosed herein are of
broad applicability across a wide range of enamide structures. Exemplary
reagents and reaction conditions for the conversion of the enamide to the
amide are set forth below.

Catalyst

[0075] The carbon-carbon double bonds of the enamides are reduced by
processes such as hydrogen transfer, in which a hydrogen-donor such as a
secondary alcohol, and in particular isopropanol is used; and
hydrogenation, in which molecular hydrogen is used. Both hydrogen
transfer and hydrogenation processes require a catalyst or catalytic
system to activate the reducing agent, namely an alcohol or molecular
hydrogen, respectively.

[0076] In selected embodiments of the present invention, the enamide
substrate is chiral or prochiral and the reduction, hydrogen transfer or
hydrogenation is performed in a stereoselective manner. In this
embodiment, it is generally preferred that the catalyst is a chiral
catalyst. Also preferred is that the chiral catalyst is a transition
metal catalyst.

[0078] In a preferred embodiment, the metal in the catalyst is rhodium
(Rh), ruthenium (Ru) or iridium (Ir).

[0079] In an exemplary embodiment, the hydrogenation catalyst used in the
present methods is a chiral complex of a transition metal with a chiral
phosphine ligand, including monodentate and bidentate ligands. For
example, preferred bidentate ligands include
1,2-bis(2,5-dimethylphospholano)ethane (MeBPE),
P,P-1,2-phenylenebis{(2,5-endo-dimethyl)-7-phosphabicyclo[2.2.1]heptane}
(MePennPhos), 5,6-bis(diphenylphosphino) bicyclo[2.2.1]hept-2-ene
(NorPhos) and 3,4-bis(diphenylphosphino) N-benzyl pyrrolidine
(commercially available as catASium® D).

[0081] The catalyst is present in the reaction mixture in any useful
amount. Determining an appropriate catalyst structure and an effective
amount of this catalyst is well within the abilities of those skilled in
the art. In an exemplary embodiment, the catalyst is present in an amount
of from about 0.005 mol % to about 1 mol % Generally, it is preferred
that the catalyst be present in an amount of from about 0.01 mol % to
about 0.5 mol % and, even more preferably, from about 0.02 mol % to about
0.2 mol %.

[0082] In an exemplary embodiment, the enamide is hydrogenated to the
corresponding amide in the presence of from about 0.02 to about 0.3 mol
%, preferably, from about 0.03 to about 0.2 mol %, and even more
preferably, from about 0.03 to about 0.1 mol % Rh-MeBPE catalyst.

[0083] In another exemplary embodiment, the enamide is hydrogenated to
give the amide in the presence of about 0.1 to about 1.0 mol %,
preferably about 0.1 to about 0.5 mol % and, more preferably about 0.3
mol % of a Rh-PennPhos catalyst.

[0084] In another exemplary embodiment, the enamide is hydrogenated to
give the amide in the presence of about 0.005 to about 1.0 mol %,
preferably about 0.01 to about 0.5 mol % and, more preferably about 0.02
to about 0.1 mol % of (R,R)-NorPhos(COD)RhBF4 catalyst.

[0085] A presently preferred catalyst of use in the invention provides the
amide in a high yield of at least 85%, preferably at least 90% and more
preferably at least 95% yield from the enamide. A generally preferred
catalyst is one that provides high yields of amides when the synthesis is
on a large scale of at least 300 grams, preferably at least 500 grams,
more preferably at least 750 grams and even still more preferably at
least 1,000 g. Preferred catalysts provide the amides in the high yield
set forth above when the reaction is carried out on the large scale, also
set forth above. An exemplary catalyst having these desirable properties
is (R,R)-NorPhos(COD)RhBF4.

Hydrogen Pressure

[0086] When the conversion of the C--C double bond of the enamide to the
corresponding C--C single bond is effected by hydrogenation, the pressure
of the hydrogen in the reaction vessel can be adjusted to optimize the
reaction yield and stereoselectivity. The methods of the invention are
practiced with any useful hydrogen pressure, and those with skill in the
art will understand how to adjust the hydrogen pressure to optimize the
desired result.

[0087] In an exemplary embodiment, the enamide is hydrogenated, to afford
the amide, at a hydrogen pressure of about 2 to about 10 bar, preferably
about 4 to about 8 bar and, more preferably, about 5 to about 6 bar.

Solvent

[0088] The methods of the invention are not limited to practice with any
one solvent or any class of solvents, e.g. protic, aprotic, aromatic, or
aliphatic. Choice of an appropriate solvent for a particular reaction is
well within the abilities of those of skill in the art.

[0089] In an exemplary embodiment, the enamide is converted to the amide
in the presence of a solvent, which is a protic solvent, an aprotic
solvent, or a mixture thereof. In a preferred embodiment the solvent is a
protic solvent, which is an alcohol, more preferably, a C1 to
C4-alcohol. In other preferred embodiments, the alcohol is methanol,
ethanol, n-propanol, iso-propanol, n-butanol, 2-butanol, or
2,2,2-trifluoroethanol (CF3CH2OH). In a presently preferred
embodiment, the alcohol is iso-propanol.

[0090] In another exemplary embodiment, the aprotic solvent is an aromatic
solvent, a non-aromatic solvent or a mixture thereof. Exemplary aromatic
solvents of use in the present invention include toluene, benzene, and
xylene, and preferably less toxic aromatic solvents such as toluene and
xylene. Exemplary non-aromatic solvents of use in the methods of the
invention include tetrahydrofuran (THF), dichloromethane
(CH2Cl2), ethyl acetate (EtOAc), and acetonitrile (CH3CN).

[0091] The solvent and substrate are present in essentially any useful
ratio. In an exemplary embodiment, the solvent and substrate are present
in amounts that provide a substrate solution of from about 0.05 M to
about 0.5 M, preferably, from about 0.1 M to about 0.3 M and, more
preferably, from about 0.12 M to about 0.34 M.

Amide

[0092] The amides formed by the methods of the invention have diverse
structures and can include alkyl, heteroalkyl, aryl and heteroaryl
substructures. In an exemplary embodiment, the amide has the formula:

##STR00015##

in which R1-R3 and R5 are as discussed above.

[0093] As discussed previously, the methods of the invention are useful
for preparing amides that include within their structure the
1,2,3,4-tetrahydro-N-alkyl-1-naphthalenamine or
1,2,3,4-tetrahydro-1-naphthalenamine substructure. Thus, in an exemplary
embodiment, the amide has the formula:

##STR00016##

in which R4 and R5 are as described above.

[0094] An exemplary amide is a trans amide, having the formula:

##STR00017##

[0095] A further exemplary amide has the formula:

##STR00018##

[0096] In a preferred embodiment, the amide has the formula:

##STR00019##

In each of the amide formulae above, C-1 and C-4 have a configuration
independently selected from (R) and (S), and in a preferred embodiment,
C-1 is of (R)-configuration, and C-4 is of (S)-configuration.

Enantiomeric or Diastereomeric Excess

[0097] In a preferred embodiment, the enantiomeric excess (ee) of a
desired enantiomer or the diastereomeric excess (de) of a desired
diastereomer produced by the present method is from about 60% ee/de to
about 99% ee/de, preferably from about 70% ee/de to about 99% ee/de, more
preferably, from about 80% ee/de to about 99% ee/de, still more
preferably, from about 90% ee/de to about 99% ee/de.

[0098] In another preferred embodiment, the invention provides an amide
having an enantiomeric or diastereomeric excess of at least about 99%,
preferably, at least about 99.4% and, more preferably, at least about
99.8%. Amides that are essentially free of their optical antipodes are
accessible through the methods of the invention.

[0099] When using rhodium catalyst systems based on chiral bidentate
ligands, such as those derived from 1,2-bis(phospholano)ethane (BPE)
ligands, P,P-1,2-phenylenebis(7-phosphabicyclo[2.2.1]heptane) (PennPhos)
ligands, 5,6-bis(phosphino)bicyclo[2.2.1]hept-2-ene (NorPhos) ligands, or
3,4-bis(phosphino) pyrrolidine (commercially available as catASium®
D) ligands, the diastereomeric purity of the trans amide derived from the
corresponding enamide is surprisingly high.

[0100] In a preferred embodiment, when the amide includes the
1,2,3,4-tetrahydro-N-alkyl-1-naphthalenamine or
1,2,3,4-tetrahydro-1-naphthalenamine subunit, the method provides
(1R,4S)-trans amide, which is substantially free of its cis isomer.

[0101] In one exemplary embodiment, the enamide is hydrogenated at about 4
to about 6 bar hydrogen pressure using about 0.03 to about 0.05 mol % of
a Rh-Me-BPE catalyst in isopropanol, to give the trans N-acetyl amide in
about 80 to about 99% de, preferably at least 95% de, and more preferably
at least 99% de.

[0102] In another exemplary embodiment, the enamide is hydrogenated at
about 4 to about 5 bar hydrogen pressure, using about 0.2 to about 0.5
mol % of a Rh-PennPhos catalyst in isopropanol, to give the trans
N-acetyl amide in about 80 to about 99% de, preferably at least 95% de,
and more preferably at least 99% de.

[0103] In yet another exemplary embodiment the enamide is hydrogenated at
about 5 to about 8 bar hydrogen pressure, using about 0.01 to about 0.05
mol % of (R,R)NorPhos(COD)RhBF4 catalyst in isopropanol to give the
trans N-acetyl amide in about 80-99% de, preferably at least 95% de, and
more preferably at least 99% de.

[0104] In a preferred embodiment, the hydrogenation is carried out at an
enamide concentration of about 0.1 M to about 0.3 M.

[0105] In a further exemplary embodiment, the stereoisomerically enriched
amide is purified, or further enriched, by selective crystallization. In
another exemplary embodiment, the amide is purified, or enriched, to an
enantiomeric or diastereomeric purity of about 90 to about 99% ee/de. In
another exemplary embodiment, the amide is purified, or enriched, to an
enantiomeric or diastereomeric purity of about 95 to about 99% ee/de.

[0106] The product of the hydrogenation or hydrogen transfer can be
enantiomerically or diastereomerically enriched by methods known in the
art, e.g., chiral chromatography, selective crystallization and the like.
It is generally preferred that the enrichment afford a product at least
about 95% of which is a single stereoisomer. More preferably, at least
about 97%, still more preferably at least about 99% is a single
stereoisomer.

[0107] In a presently preferred embodiment, the enriched trans amide is
purified, or enriched, by selective crystallization, affording the
desired trans isomer in about 99% de.

C. Amide to Amine

[0108] In another aspect, the current invention provides methods for
converting an amide formed from the corresponding enamide to an amine. In
an exemplary embodiment, the method includes contacting the amide with a
deacylating reagent under conditions appropriate to deacylate the amide,
thereby forming an amine.

[0109] In an exemplary embodiment, the amine has the formula:

##STR00020##

or a salt thereof. The radicals have the identities set forth above.

[0110] The amine can be of any desired structure, however, it is
preferably a chiral amine. When the amine is chiral, the enantiomeric
excess (ee) of a desired enantiomer or the diastereomeric excess (de) of
a desired diastereomer produced by the present method is from about 60%
ee/de to about 99% ee/de, preferably from about 70% ee/de to about 99%
ee/de, more preferably, from about 80% ee/de to about 99% ee/de, still
more preferably, from about 90% ee/de to about 99% ee/de.

[0111] In another preferred embodiment, the invention provides an amine
having an enantiomeric or diastereomeric excess of at least about 99%,
preferably, at least about 99.4% and, more preferably, at least about
99.8%. Amines that are essentially free of their optical antipodes are
accessible through the methods of the invention.

[0112] In an exemplary embodiment, the amine includes the
1,2,3,4-tetrahydro-N-alkyl-1-naphthalenamine or
1,2,3,4-tetrahydro-1-naphthalenamine substructure, and has the formula:

##STR00021##

or a salt thereof.

[0113] In a preferred embodiment, the amine is a trans amine, having the
formula:

##STR00022##

or a salt thereof.

[0114] An exemplary amine has the formula:

##STR00023##

in which Q.sup.- is an anion. The index e is a number from 0 to 1. The
index may take a fractional value, indicating that the amine salt is a
hemi-salt.

[0115] In a preferred embodiment, the amine has the formula:

##STR00024##

wherein Q.sup.- and e are as described above.

[0116] C-1 and C-4 have a configuration independently selected from (R)
and (S). Preferably C-1 is of (R)-configuration, and C-4 is of
(S)-configuration.

[0117] In another preferred embodiment, the amine is in the trans
configuration and is substantially free of the cis isomer.

[0118] The amide is deacylated by any suitable process. Many methods of
deacylating amides to the corresponding amines are known in the art. In
an exemplary embodiment, the deacylating reagent is an enzyme. Exemplary
enzymes of use in this process include those of the class EC 3.5.1 (e.g.,
amidase, aminoacylase), and EC 3.4.19.

[0119] In another embodiment, the deacylating reagent is an acid or a
base. The acid or base can be either inorganic or organic. Mixtures of
acids or mixtures of bases are useful as well. When the deacylating
reagent is an acid, it is generally preferred that the acid is selected
so that the acid hydrolysis produces a product that is a form of the
amine. In an exemplary embodiment, the acid is hydrochloric acid (HCl).

[0120] Other deacylating conditions of use in the present invention
include, but are not limited to, methanesulfonic acid/HBr in alcoholic
solvents, triphenylphosphite/halogen (e.g., bromine, chlorine) complex
and a di-t-butyl dicarbonate/lithium hydroxide sequence.

[0121] In a preferred embodiment, the amide is deacylated by treatment
with an activating agent, e.g., trifluoromethanesulfonic anhydride,
phosgene, and preferably, oxalyl chloride/pyridine. The reaction is
quenched with an alcohol, preferably a glycol, e.g., propylene glycol.

[0122] When the amide includes the
1,2,3,4-tetrahydro-N-alkyl-1-naphthalenamine or
1,2,3,4-tetrahydro-1-naphthalenamine substructure, the deacylation
conditions preferably are selected such that formation of any
dihydronaphthalene side products are minimized.

[0123] The amine can be isolated or enriched. A currently preferred method
of isolating or enriching the amine includes at least one step of
selective crystallization.

[0124] The amine is optionally N-alkylated or N-acylated to prepare the
corresponding N-alkyl or N-acyl derivative.

[0125] In an exemplary embodiment, the invention provides a method
suitable for the large scale preparation of trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine 5 and salt
forms thereof. In an exemplary embodiment, the process involves the
synthesis of an enamide, e.g. enamide 3, starting from optically pure
(4S)-tetralone 1 via the oxime 2, and subjecting enamide 3 to catalytic
asymmetric hydrogenation to afford amide 4, which upon N-deacylation
affords trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine
5, or a salt thereof (Scheme 2).

##STR00025##

[0126] In a preferred embodiment, the compound prepared by the route of
Scheme 2 is (1R,4S)-trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine. Even more
preferred is the preparation of the compound substantially free of its
cis isomer.

[0127] Compounds according to formula 5 include stereoisomers of
desmethylsertraline. The N-methyl analog of 5 is a stereoisomer of
sertraline.

[0128] The primary clinical use of sertraline is in the treatment of
depression. In addition, U.S. Pat. No. 4,981,870 discloses and claims the
use of sertraline and related compounds for the treatment of psychoses,
psoriasis, rheumatoid arthritis and inflammation.

[0129] (1R,4S)-trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine and
(1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine
are useful in the treatment of CNS-related disorders that are modulated
by monoamine activity (U.S. Patent Application No. 2004/0092605 to
Jerussi et al.; cited references). Those CNS-related disorders include
mood disorders (e.g. depression), anxiety disorders (e.g., OCD),
behavioral disorders (e.g. ADD and ADHD), eating disorders, substance
abuse disorders and sexual function disorders. Potentially, these
molecules produce diminished side effects as compared to the current
standards of treatment. The compounds are also useful for the prophylaxis
of migraine.

IV. Compositions

[0130] In another aspect, the invention provides a mixture comprising:

##STR00026##

in which R4 is a member selected from substituted or unsubstituted
aryl and substituted or unsubstituted heteroaryl. Q.sup.- is an anion.
The indices e and f independently represent a number from 0 to 1. Thus,
the structures above encompass hemi-salts.

[0131] The indices x and y are independently selected from (S) and (R). In
one embodiment, when x is (S), y is (S) and when x is (R), y is (R). In
another embodiment, when x is (S), y is (R).

[0132] In an exemplary embodiment, R4 is substituted or unsubstituted
aryl. A preferred aryl moiety is a substituted or unsubstituted phenyl
moiety.

[0133] In another exemplary embodiment, the mixture comprises compounds
with the following formulae:

##STR00027##

in which e, f, x and y are as described above.

[0134] The mixtures set forth above are of use in pharmaceutical
formulations. It is generally recognized that stereoisomers of bioactive
compounds may have different properties. For example, the S-enantiomer of
the beta-adrenergic blocking agent, propranolol, is known to be 100 times
more potent than the R-enantiomer. However, potency is not the only
concern in the field of pharmaceuticals. Optical purity is important
since certain isomers may actually be deleterious rather than simply
inert. Mixtures of diastereomers effectively combine and modulate the
properties of each of the pure diastereomers. Thus, in selected
embodiments, the invention provides mixtures of diastereomeric compounds
A and B.

[0135] According to the present invention, a therapeutically effective
amount of A or B, which may be a pure isomer or a mixture of any A and B,
may also be administered to a person in need of therapy.

[0137] In addition to their beneficial therapeutic effects, compounds
prepared by methods of the present invention may provide the additional
benefit of avoiding or reducing one or more of the adverse effects
associated with conventional mood disorder treatments. Such side effects
include, for example, insomnia, breast pain, weight gain, extrapyramidal
symptoms, elevated serum prolactin levels and sexual dysfunction
(including decreased libido, ejaculatory dysfunction and anorgasmia).

[0138] The compounds (and their mixtures) prepared by the methods of the
present invention are also effective for treating disruptive behavior
disorders, such as attention deficit disorder (ADD) and attention
deficit/hyperactivity disorder (ADHD), which is in accordance with its
accepted meaning in the art, as provided in the DSM-1V-TR®. These
disorders are defined as affecting one's behavior resulting in
inappropriate actions in learning and social situations. Although most
commonly occurring during childhood, disruptive behavior disorders may
also occur in adulthood.

[0139] The term "treating" when used in connection with the foregoing
disorders means amelioration, prevention or relief from the symptoms
and/or effects associated with these disorders and includes the
prophylactic administration of a compound of formula A or B, a mixture
thereof, or a pharmaceutically acceptable salt of either, to
substantially diminish the likelihood or seriousness of the condition.

[0140] Pure compounds and mixtures prepared by the methods of the present
invention are also effective for treating eating disorders. Eating
disorders are defined as a disorder of one's appetite or eating habits or
of inappropriate somatotype visualization. Eating disorders include, but
are not limited to, anorexia nervosa; bulimia nervosa, obesity and
cachexia.

[0141] Mood disorders, such as depressive disorders, e.g., dysthymic
disorder or major depressive disorder; bipolar disorders, e.g., bipolar I
disorder, bipolar II disorder, and cyclothymic disorder; mood disorder
due to a general medical condition with depressive, and/or manic
features; and substance-induced mood disorder can be treated using
compounds and mixtures of the invention.

[0142] Anxiety disorders, such as acute stress disorder, agoraphobia
without history of panic disorder, anxiety disorder due to general
medical condition, generalized anxiety disorder, obsessive-compulsive
disorder, panic disorder with agoraphobia, panic disorder without
agoraphobia, posttraumatic stress disorder, specific phobia, social
phobia, and substance-induced anxiety disorder are treatable with
compounds and mixtures of the invention.

[0143] Compounds and mixtures prepared by methods of the invention are
also effective for treating cerebral function disorders. The term
cerebral function disorder, as used herein, includes cerebral function
disorders involving intellectual deficits, and may be exemplified by
senile dementia, Alzheimer's type dementia, memory loss, amnesia/amnestic
syndrome, epilepsy, disturbances of consciousness, coma, lowering of
attention, speech disorders, Parkinson's disease and autism.

[0144] The compounds and mixtures are also of use to treat schizophrenia
and other psychotic disorders, such as catatonic, disorganized, paranoid,
residual or differentiated schizophrenia; schizophreniform disorder;
schizoaffective disorder; delusional disorder; brief psychotic disorder;
shared psychotic disorder; psychotic disorder due to a general medical
condition with delusions and/or hallucinations.

[0145] The compounds of formulae A and B are also effective for treating
sexual dysfunction in both males and females. Disorders of this type
include, for example, erectile dysfunction and orgasmic dysfunction
related to clitoral disturbances.

[0146] Compounds and mixtures prepared by the methods of the present
invention are also useful in the treatment of substance abuse, including,
for example addiction to cocaine, heroin, nicotine, alcohol, anxiolytic
and hypnotic drugs, cannabis (marijuana), amphetamines, hallucinogens,
phenylcyclidine, volatile solvents, and volatile nitrites. Nicotine
addiction includes nicotine addiction of all known forms, such as, for
example, nicotine addiction resulting from cigarette, cigar and/or pipe
smoking, as well as addiction resulting from tobacco chewing. In this
respect, due to their activity as norepinephrine and dopamine uptake
inhibitors, the compounds of the present invention can function to reduce
the craving for the nicotine stimulus. Bupropion (ZYBAN®,
GlaxoSmithKline, Research Triangle Park, N.C., USA) is a compound that
has activity at both norepinephrine and dopamine receptors, and is
currently available in the United States as an aid to smoking cessation
treatment. As a benefit beyond the therapeutic activity of buproprion,
however, the compounds of the present invention provide an additional
serotonergic component.

[0147] Pure compounds and mixtures prepared by the methods of the present
invention are also effective in the prophylaxis of migraine.

[0148] Compounds and mixtures prepared by the methods of the present
invention are also useful in the treatment of pain disorders, including
for example fibromyalgia, chronic pain, and neuropathic pain. The term
"fibromyalgia" describes several disorders, all characterized by achy
pain and stiffness in soft tissues, including muscles, tendons, and
ligaments. Various alternative terms for fibromyalgia disorders have been
used in the past, including generalized fibromyalgia, primary
fibromyalgia syndrome, secondary fibromyalgia syndrome, localized
fibromyalgia, and myofascial pain syndrome. Previously, these disorders
were collectively called fibrositis or fibromyositis syndromes.
Neuropathic pain disorders are thought to be caused by abnormalities in
the nerves, spinal cord, or brain, and include, but are not limited to:
burning and tingling sensations, hypersensitivity to touch and cold,
phantom limb pain, postherpetic neuralgia, and chronic pain syndrome
(including, e.g., reflex sympathetic dystrophy and causalgia).

[0149] The magnitude of a prophylactic or therapeutic dose of a compound
of formulae A, B or mixtures thereof will vary with the nature and
severity of the condition to be treated and the route of administration.
The dose, and perhaps the dose frequency, will also vary according to the
age, body weight and response of the individual patient. In general, the
total daily dose ranges of compounds of the present invention will be
from about 1 mg per day to about 500 mg per day, preferably about 1 mg
per day to about 200 mg per day, in single or divided doses. Dosages of
less than 1 mg per day of compounds of the invention are also within the
scope of the instant invention.

[0150] Any suitable route of administration may be employed. For example,
oral, rectal, intranasal, and parenteral (including subcutaneous,
intramuscular, and intravenous) routes may be employed. Dosage forms can
include tablets, troches, dispersions, suspensions, solutions, capsules
and patches.

[0151] Pharmaceutical compositions of the present invention include as
active ingredient, a single compound, or a mixture of compounds, of
formula A or B, or a pharmaceutically acceptable salt of A or B, together
with a pharmaceutically acceptable carrier and, optionally, with other
therapeutic ingredients.

[0152] The pharmaceutically acceptable carrier may take a wide variety of
forms, depending on the route desired for administration, for example,
oral or parenteral (including intravenous). In preparing the composition
for oral dosage form, any of the usual pharmaceutical media may be
employed, such as, water, glycols, oils, alcohols, flavoring agents,
preservatives, and coloring agents in the case of oral liquid
preparation, including suspension, elixirs and solutions. Carriers such
as starches, sugars, microcrystalline cellulose, diluents, granulating
agents, lubricants, binders and disintegrating agents may be used in the
case of oral solid preparations such as powders, capsules and caplets,
with the solid oral preparation being preferred over the liquid
preparations. Preferred solid oral preparations are tablets or capsules,
because of their ease of administration. If desired, tablets may be
coated by standard aqueous or nonaqueous techniques. Oral and parenteral
sustained release dosage forms may also be used.

[0153] Exemplary formulations, are well known to those skilled in the art,
and general methods for preparing them are found in any standard pharmacy
school textbook, for example, Remington, THE SCIENCE AND PRACTICE OF
PHARMACY, 21st Ed., Lippincott.

[0154] Thus, as set forth herein, the invention is exemplified by the
following aspects and embodiments.

[0155] A method for converting an oxime into an enamide. The method
includes, (a) contacting the oxime with a phosphine and an acyl donor,
under conditions appropriate to convert the oxime into the enamide.

[0156] The method according to the preceding paragraph in which the oxime
has the formula:

##STR00028##

wherein R1, R2 and R3 are members independently selected
from H, substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl and substituted or unsubstituted
heterocycloalkyl. At least two of R1, R2 and R3 are
optionally joined to form a ring system selected from substituted or
unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heteroaryl.

[0157] The method of any of the preceding paragraphs in which the oxime
has the formula:

##STR00029##

wherein Ar is a member selected from substituted or unsubstituted aryl
and substituted or unsubstituted heteroaryl. R4 is a member selected
from H, substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl and substituted or unsubstituted
heterocycloalkyl; and, the index a is selected from the integers from 1
to 4.

[0158] The method of any of the preceding paragraphs in which R4 is
substituted or unsubstituted aryl.

[0159] The method of any of the preceding paragraphs in which R4 is
substituted or unsubstituted phenyl.

[0160] The method of any of the preceding paragraphs in which R4 is
phenyl substituted with at least one halogen.

[0161] The method of any of the preceding paragraphs in which R4 has
the formula:

##STR00030##

wherein X1 and X2 are independently selected halo moieties.

[0162] The method of any of the preceding paragraphs in which X1 and
X2 are each chloro.

[0163] The method of any of the preceding paragraphs in which Ar is
substituted or unsubstituted phenyl.

[0164] The method of any of the preceding paragraphs in which the oxime
has the formula:

##STR00031##

[0165] The method of any of the preceding paragraphs in which acyl donor
has the formula: Z--C(O)--R5, wherein Z is a leaving group. R5
is a member selected from H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl and substituted or
unsubstituted heterocycloalkyl.

[0166] The method according any of the preceding paragraphs in which Z has
the formula:

R6--C(O)--O--

wherein R6 is a member selected from substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl and
substituted or unsubstituted heterocycloalkyl.

[0167] The method according to any of the preceding paragraphs in which
both R5 and R6 are independently selected substituted or
unsubstituted C1-C4 moieties.

[0168] The method according to any of the preceding paragraphs in which
the phosphine has the formula:

P(Q)3

wherein each Q is a member independently selected from H, substituted or
unsubstituted alkyl and substituted or unsubstituted aryl.

[0169] The method according to any of the preceding paragraphs in which
each Q is a member independently selected from substituted or
unsubstituted C1-C6 alkyl.

[0170] The method according to any of the preceding paragraphs in which
the contacting is in solution with an aprotic solvent.

[0171] The method according to any of the preceding paragraphs in which
the aprotic solvent is an aromatic solvent.

[0172] The method according to any of the preceding paragraphs in which
the aprotic aromatic solvent is selected from toluene, xylene and
combinations thereof.

[0173] The method according to any of the preceding paragraphs in which
enamide has the formula:

##STR00032##

[0174] The method according to any of the preceding paragraphs in which
C-4 has a configuration selected from R, S and mixtures thereof.

[0175] The method according to any of the preceding paragraphs in which
C-4 is of S configuration.

[0176] The method according to any of the preceding paragraphs further
including: (b) contacting the enamide formed in step (a) with a
hydrogenation catalyst and hydrogen or hydrogen transfer reagent under
conditions appropriate to hydrogenate a carbon-carbon double bond of the
enamide, thereby converting the enamide to an amide.

[0177] The method according to any of the preceding paragraphs in which
the catalyst is a chiral catalyst.

[0178] The method according to any of the preceding paragraphs in which
the chiral catalyst is a complex of a transition metal with a chiral
phosphine ligand.

[0179] The method according to any of the preceding paragraphs in which
the amide is a racemic or chiral amide.

[0180] The method according to any of the preceding paragraphs in which
amide has the formula:

##STR00033##

[0181] The method according to any of the preceding paragraphs in which
C-1 and C-4 have a configuration independently selected from R and S.

[0182] The method according to any of the preceding paragraphs in which
C-1 is of R configuration; and C-4 is of S configuration.

[0183] The method according to any of the preceding paragraphs further
including: (c) contacting the amide with a deacylating reagent under
conditions appropriate to deacylate --HNC(O)R5 of the amide, thereby
forming an amine.

[0184] The method according to any of the preceding paragraphs including:
(d) isolating said amine.

[0185] The method according to any of the preceding paragraphs in which
isolating comprises selective crystallization.

[0186] The method according to any of the preceding paragraphs in which
the amine has the formula:

##STR00034##

wherein Q.sup.- is an anion; and e is 0 to 1.

[0187] The method according to any of the preceding claims in which C-1
and C-4 have a configuration independently selected from R and S.

[0188] The method according to any preceding claims in which C-1 is of R
configuration; and C-4 is of S configuration.

[0189] A method of converting an oxime having the formula

##STR00035##

into an enamide having the formula:

##STR00036##

wherein R4 is selected from substituted or unsubstituted aryl and
substituted or unsubstituted heteroaryl. R5 is selected from H,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl and substituted or unsubstituted
heterocycloalkyl. The method includes: (a) contacting the oxime with a
phosphine and an acyl donor under conditions appropriate to convert the
oxime to the enamide.

[0190] The method according to the preceding paragraph in which C-4 is of
S configuration.

[0191] The method according to the preceding paragraphs in which the
phosphine is a trialkylphosphine.

[0192] The method according to the preceding paragraphs in which the
oxime, the acyl donor and the phosphine are dissolved in an aromatic
solvent.

[0193] The method according to the preceding paragraphs in which the acyl
donor is an alkyl anhydride.

[0194] The method according to the preceding paragraphs including: (b)
contacting the enamide formed in step (a) with a chiral hydrogenation
catalyst and hydrogen under conditions appropriate to hydrogenate a
carbon-carbon double bond conjugated to C(O) of the enamide, thereby
converting the enamide to an amide having the formula:

##STR00037##

wherein C-1 has a configuration selected from R and S.

[0195] The method according to the preceding paragraphs in which the
chiral catalyst includes rhodium complexed to a chiral phosphine ligand.

[0196] The method according to the preceding paragraphs further including:
(c) contacting the amide with a deacylating reagent under conditions
appropriate to deacylate --HNC(O)R5 of the amide, thereby forming an
amine having the formula:

##STR00038##

wherein Q.sup.- is an anion. The index e is 0 or 1.

[0197] The method according to the preceding paragraphs in which the
deacylating reagent is an enzyme.

[0198] The method according to the preceding paragraphs in which the
deacylating reagent is an acid.

[0199] A mixture comprising:

##STR00039##

wherein R4 is a member selected from substituted or unsubstituted
aryl and substituted or unsubstituted heteroaryl. Q.sup.- is an anion.
The indices e and f are independently selected numbers from 0 to 1; and x
and y are selected from R and S, such that when x is R, y is R, and when
x is S, y is S.

[0200] The mixture according to the preceding paragraph in which A is
present in the mixture in a diastereomeric excess of at least 90%
relative to B.

[0201] The mixture according to the preceding paragraphs in which A is
present in said mixture in a diastereomeric excess of at least 98%
relative to B.

[0202] The mixture according to the preceding paragraphs in which x and y
are R.

[0203] The mixture according to the preceding paragraphs in which x and y
are S.

[0204] The mixture according to the preceding paragraphs in which R4
is substituted or unsubstituted phenyl.

[0205] A pharmaceutical formulation including a mixture according to the
preceding paragraphs.

[0206] The following examples are provided to illustrate selected
embodiments of the invention and are not to be construed as limiting its
scope.

[0207] A suspension formed from a mixture of (S)-tetralone 1 (56.0 g,
0.192 mol), hydroxylamine hydrochloride (14.7 g, 0.212 mol), and sodium
acetate (17.4 g, 0.212 mol) in methanol (168 mL) was heated to reflux for
1 to 5 hours under a N2 atmosphere. The progress of the reaction was
monitored by HPLC. After the reaction was complete, the reaction mixture
was concentrated in vacuo. The residue was diluted with toluene (400 mL)
and 200 mL water. The organic layer was separated and washed with an
additional 200 mL water. The organic layer was concentrated and dried to
give crude solid oxime 2 (58.9 g, 100%), m. p. 117-120° C.

[0209] The solution of the crude oxime 2 (59 g, 0.193 mol) in toluene (500
mL) was purged with N2 for 30 min. Et3P (25 g, 0.212 mol) was
charged. After stirring for 10 min, acetic anhydride (21.6 g, 20 mL,
0.212 mol) was added. The reaction mixture was refluxed for 8 to 13 h.
Progress of the reaction was monitored by HPLC. The reaction mixture was
cooled to room temperature. 6N NaOH (aq) (86 mL, 0.516 mol) and 1.0 M
(n-Bu)4NOH in methanol (1.0 mL) were added. The hydrolysis was
complete in about 2 to 4 h. The organic layer was separated and diluted
with EtOAc (300 mL) and 2-BuOH (30 mL). The diluted organic solution was
washed with 1% HOAc (aq) solution (300 mL) and DI water (3×300 mL)
and concentrated to about 350 mL of a slurry in vacuo. The slurry was
diluted with heptane (100 mL) and 2-BuOH (4 mL) and heated to reflux to
form a clear solution. Heptane (50 to 200 mL) was slowly added until a
cloudy solution formed. The suspension was slowly cooled to rt. The
product was filtered out, washed with 30% toluene and 70% heptane
(3×100 mL) solution and dried in a vacuum oven to give 56.9 g white
solid (enamide 3, 89% yield), m. p. 167-168° C.

[0210] (S)-Tetralone 1 (50.0 g, 0.172 mol) was slurried in methanol (150
mL) with hydroxylamine hydrochloride (13.1 g, 0.189 mol) and sodium
acetate (15.5 g, 0.189 mol). The resulting suspension was heated to
reflux for 2 to 6 h under an inert atmosphere with progress monitored by
HPLC. On completion, the mixture was cooled to 25° C., diluted
with toluene (300 mL) and quenched with 1.7 N NaOH (100 mL). The mixture
was concentrated in vacuo under reduced pressure, the aqueous layer
removed and the organic layer washed further with DI water (100 mL).
Further toluene (300 mL) was charged to the vessel and water removed by
azeotropic distillation. Once at ambient temperature, n-Bu3P (47.1
mL, 0.183 mol) was charged to the reactor, followed by acetic anhydride
(32.5 mL, 0.344 mol). The reaction was heated to reflux and monitored by
HPLC. After 20-24 h, the reaction was cooled to ambient temperature and
quenched with 6 N NaOH (120 mL). This mixture was allowed to react for 2
to 6 h before the aqueous layer was removed. The organic phase was washed
with DI water (100 mL). Concentration of the mixture in vacuo, cooling to
room temperature and diluting with isopropanol (50 mL) was done prior to
addition of heptane to assist with crystallization. An initial charge of
heptane (50 mL) was followed by an additional 650 mL. Aging of the slurry
followed by filtration, washing (4×100 mL heptane) and drying
yielded a light yellow solid (enamide 3, 44.1 g, 77%).

[0212] The enamide 3 (24 g, 72 mmol) was slurried in degassed isopropanol
(200 mL). The resulting slurry was transferred to the appropriate
reactor. Prior to the addition of the catalyst solution, the content of
the reactor was purged with nitrogen. A solution of
(R,R)-MeBPE(COD)RhBF4 catalyst (20.1 mg, 0.036 mmol, 0.05 mol %) in
isopropanol (IPA) (100 mL) was added to the reactor. The content was
cooled to 0° C. and purged with nitrogen three times. The reactor
was then purged with hydrogen and pressurized to 90 psig. The reaction
was aged with agitation at 0° C. for 7.5 h and conversion was
monitored by the hydrogen uptake. The content was then warmed to RT and
hydrogen was vented. After purging with nitrogen, the contents were
drained. The reaction mixture was heated to 50° C. and filtered
through a pad of Celite. The clear orange solution was concentrated to
˜50% volume (150 mL) and diluted with toluene (5.9 g, 5 wt %). The
suspension was heated to 65° C. and water (14.7 mL) was added
dropwise to form a cloudy solution. The slurry was slowly cooled to
-10° C. and aged for 30 minutes. The solid was filtered and washed
with cold IPA (2×45 mL). The cake was dried under vacuum at
45° C. overnight to afford 20.0 g (83% yield) of trans acetamide 4
(>99% de).

[0214] A solution of trans-acetamide 4 (9.0 g, 26.9 mmol), n-propanol (45
mL) and 5M hydrochloric acid (45 mL) was refluxed for approximately 48 h
(90-93° C.). During this time, the reaction temperature was
maintained at ≧90° C. by periodically collecting the
distillate until the reaction temperature was >92° C.
Additional n-propanol was added periodically to maintain the solution at
its original volume. After the hydrolysis was complete, the solution was
slowly cooled to 0° C., resulting in a slurry, which was aged for
one hour at 0° C. The reaction mixture was filtered, and the cake
was washed with 1:1 methanol/water (20 mL), followed by t-butyl methyl
ether (20 mL). The wet-cake was dried under vacuum at 45 to 50° C.
to afford 7.0 g of the amine hydrochloride 5 (80% yield).

[0216] Oxime 2 was acylated in situ to afford the intermediate 2A, which
undergoes reductive acylation to provide a mixture of the acylated
enamide 3 and the diacylated analog 3A. The reaction was carried out in
either toluene or o-xylene at reflux. The mixture of 3 and 3A was then
treated with an aqueous solution of base such as sodium hydroxide or
sodium carbonate, with or without a phase transfer catalyst (e.g.
tetrabutylammonium hydrogen sulfate/hydroxide), to convert the
intermediate 3A to the desired enamide 3. Exemplary reaction conditions
for the conversion of oxime 2 to enamide 3 are shown in Schemes 3a and 3
b.

##STR00040##

##STR00041##

Example 5

Catalytic Asymmetric Hydrogenation of the Enamide 3 Using (R,S,R,S)-MePenn
Phos(COD)RhBF4 as the Catalyst

[0217] As shown in Scheme 4, the enamide 3 was subjected to homogeneous
catalytic asymmetric hydrogenation in the presence of a chiral catalyst,
H2, and a solvent. In this example the catalyst was derived from the
complex of the transition metal rhodium with the chiral phosphine ligand,
(1R,2S,4R,5S)--P,P-1,2-phenylenebis{(2,5-endo-dimethyl)-7-phosphabicyclo[-
2.2.1]heptane}(R,S,R,S-MePennPhos). The hydrogenations were carried out at
a substrate concentration of about 0.12 M to about 0.24 M of compound 3.

##STR00042##

Example 6

Catalytic Asymmetric Hydrogenation of the Enamide 3 Using (R,R)-MeBPE
Rh(COD)BF4 as the Catalyst

[0218] As shown in Scheme 5, the enamide 3 was subjected to homogeneous
catalytic asymmetric hydrogenation in the presence of a chiral catalyst,
H2, and a solvent. In this example the catalyst was derived from the
complex of the transition metal rhodium with the chiral phosphine ligand,
(R,R)-1,2-bis(2,5-dimethylphospholano)ethane (R,R-MeBPE). The
hydrogenations were carried out in the concentration range of about 0.12
M to about 0.24 M relative to the substrate 3.

##STR00043##

Example 7

Asymmetric Hydrogenation Catalyzed by (R,R)-Norphos(COD)RH-BF4

[0219] A slurry of the (S)-enacetamide,
N--((S)-4-(3,4-dichloropheyl)-3,4-dihydronaththalen-1-yl)acetamide (60.4
g, 0.18 mol), in isopropanol (595.0 g) was purged of oxygen with
vacuum/nitrogen cycles. The homogeneous catalyst precursor (referred to
as a "catalyst"), (R,R)-Norphos(COD)RH-BF4 was added as a solution in
methanol (34.6 mg, 0.025 mol %, 0.53 mL). After purging the system with
hydrogen several times, the vessel was filled with hydrogen at the
desired reaction pressure (approx 7 bar). The mixture was stirred at
25° C. and reaction progress was monitored by hydrogen uptake.
Once the reaction was judged to be complete (hydrogen uptake and HPLC),
the pressure was released and the system was purged repeatedly with
nitrogen. The light yellow slurry was diluted with isopropanol (194.7 g),
heated to dissolution (65° C.) and polish filtered. The mixture
was heated to reflux to dissolve all solids. The solution was slowly
cooled to 60-65° C. at which time the product crystallized. The
antisolvent, water (262 g), was added at about 60-65° C., then the
mixture was cooled to 0° C. over two hours and held at that
temperature for aging. Filtration of the lightly colored solid was
followed by washing with cold isopropanol (2×61 g). Drying of the
off white solid under reduced pressure at 50-55° C. provided the
(1R,4S)-acetamide in 99% de (56.6 g, 93% yield).

Example 8

Oxime and Enamide Formation

[0220] Chiral (4S)-tetralone (100.0 g, 0.34 mol) was reacted with
hydroxylamine hydrochloride (28.7 g, 0.41 mol) and sodium acetate (33.8
g, 0.41 mol) in toluene (1.37 L) for approximately 2 h at 103° C.
Water was removed from the reaction mixture by azeotropic distillation.
The reaction was quencher at 25° C. with 2 N sodium hydroxide
(167.0 g). The aqueous phase was separated and the organic phase was
washed once with water (400.0 g). Toluene (700.0 g) was added was added
and the resulting organic solution, containing the oxime, was dried by
azeotropic distillation under reduced pressure to the desired reaction
concentration. Triethylphosphine (89.0 g, 0.38 mol, 50 wt % in toluene)
is added, followed by addition of acetic anhydride (38.5 g, 0.38 mol),
which afforded the oxime acetate intermediate. The reaction mixture was
allowed to react at reflux (112-113° C.) until the remaining oxime
acetate is <2% of the product, as determined by HPLC. The reaction
mixture was cooled to 20-25° C. and the minor enimide by-product
was hydrolyzed (to enacetamide) using 6 N sodium hydroxide (210 g) in
conjunction with the phase transfer reagent, tertbutylammonium hydroxide
(5.0 g). The biphasic mixture was allowed to phase separate and the
aqueous phase was discarded. The organic phase was washed with 0.5%
acetic acid aqueous solution (67° C., 600.0 g). The aqueous phase
was removed and the organic phase was washed once with water (67°
C., 600.0 g) to remove inorganic salts. The organic phase was
concentrated and the warm solution was polish filtered to remove
additional inorganic salts. Heptanes (150 g) and 2-butanol (7.0 g) were
added and the slurry was heated to 100° C. in order to achieve
dissolution. The solution was cooled to approximately 85° C. to
initiate crystallization. Additional heptanes (190 g) were added to the
slurry at 85° C., and the mixture was then cooled to 0° C.
The slurry was aged at 0° C. for 15 min., then filtered and washed
three times with a solution consisting of a mixture of heptanes and
toluene (125 g). The product was vacuum dried at 35-45° C. 17.8 g
(89% yield) of a white crystalline solid, (S)-enacetamide was recovered.

[0221] The method according to this example was applied to a number of
substrates, the results of which are set forth in Table 1.

[0222] A solution of (1R,4S)-acetamide in dry THF (212.7 g, 239.3 mL) was
treated with dry pyridine (8.7 g, 8.9 mL, 110 mmol). The resulting clear,
colorless solution was cooled to approximately 0° C. Oxalyl
chloride (12.9 g, 8.9 mL, 101.6 mmol) was added dropwise to the strirred
solution, with care to control the exotherm and effervescence of CO and
CO2. The addition of the activating reagent was accompanied by the
formation of a slurry. The slurry was allowed to stir cold for a short
period (approx. 15 min) prior to sampling for conversion assessment. Once
the reaction was complete, dry propylene glycol was added to the
reaction, resulting in a minor exotherm. The reaction was warmed to
25° C., during which time the slurry changed in color and
consistency. HPLC analysis of a second sample showed completion before
the addition of 1-propanol (96.9 g, 120.5 mL). 6N HCl (128.0 g, 120.0 mL)
was added. The mixture was heated to effect dissolution and the resulting
mixture was polish filtered. THF was removed by atmospheric distillation.
After concentration of the mixture, it was slowly cooled to 3° C.
The resulting lightly colored slurry was filtered to yield and off-white
cake. The cake was first washed with 17 wt % n-PrOH in deionized water
(72.6 g, 75 mL total) and then with cold mtBE (55.5 g, 75 mL). The
off-white wet cake was dried under vacuum at 45-50° C. The product
was recovered as an off-white to white solid (24.8 g, 84.1% yield) with
excellent purity (>99% purity by HPLC).

[0223] All publications and patent documents cited in this application are
incorporated by reference in their entirety for all purposes to the same
extent as if each individual publication or patent document were so
individually denoted. By their citation of various references in this
document, Applicants do not admit any particular reference is "prior art"
to their invention.